Convergence in Maximum Stomatal Conductance of C3 Woody Angiosperms in Natural Ecosystems Across Bioclimatic Zones.
Stomatal conductance (g s) in terrestrial vegetation regulates the uptake of atmospheric carbon dioxide for photosynthesis and water loss through transpiration, closely linking the biosphere and atmosphere and influencing climate. Yet, the range and pattern of g s in plants from natural ecosystems across broad geographic, climatic, and taxonomic ranges remains poorly quantified. Furthermore, attempts to characterize g s on such scales have predominantly relied upon meta-analyses compiling data from many different studies. This approach may be inherently problematic as it combines data collected using unstandardized protocols, sometimes over decadal time spans, and from different habitat groups. Using a standardized protocol, we measured leaf-level g s using porometry in 218 C3 woody angiosperm species in natural ecosystems representing seven bioclimatic zones. The resulting dataset of 4273 g s measurements, which we call STraits (Stomatal Traits), was used to determine patterns in maximum g s (g smax) across bioclimatic zones and whether there was similarity in the mean g smax of C3 woody angiosperms across ecosystem types. We also tested for differential g smax in two broadly defined habitat groups - open-canopy and understory-subcanopy - within and across bioclimatic zones. We found strong convergence in mean g smax of C3 woody angiosperms in the understory-subcanopy habitats across six bioclimatic zones, but not in open-canopy habitats. Mean g smax in open-canopy habitats (266 ± 100 mmol m-2 s-1) was significantly higher than in understory-subcanopy habitats (233 ± 86 mmol m-2 s-1). There was also a central tendency in the overall dataset to operate toward a g smax of ∼250 mmol m-2 s-1. We suggest that the observed convergence in mean g smax of C3 woody angiosperms in the understory-subcanopy is due to a buffering of g smax against macroclimate effects which will lead to differential response of C3 woody angiosperm vegetation in these two habitats to future global change. Therefore, it will be important for future studies of g smax to categorize vegetation according to habitat group.


Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma.
The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications.


Meta-DNA structures.
DNA origami has emerged as a highly programmable method to construct customized objects and functional devices in the 10-100 nm scale. Scaling up the size of the DNA origami would enable many potential applications, which include metamaterial construction and surface-based biophysical assays. Here we demonstrate that a six-helix bundle DNA origami nanostructure in the submicrometre scale (meta-DNA) could be used as a magnified analogue of single-stranded DNA, and that two meta-DNAs that contain complementary 'meta-base pairs' can form double helices with programmed handedness and helical pitches. By mimicking the molecular behaviours of DNA strands and their assembly strategies, we used meta-DNA building blocks to form diverse and complex structures on the micrometre scale. Using meta-DNA building blocks, we constructed a series of DNA architectures on a submicrometre-to-micrometre scale, which include meta-multi-arm junctions, three-dimensional (3D) polyhedrons, and various 2D/3D lattices. We also demonstrated a hierarchical strand-displacement reaction on meta-DNA to transfer the dynamic features of DNA into the meta-DNA. This meta-DNA self-assembly concept may transform the microscopic world of structural DNA nanotechnology.


Cancer Anorexia and Cachexia: Screening in an Ambulatory Infusion Service and Nutrition Consultation .
Cancer anorexia-cachexia syndrome compromises physical function and nutritional and emotional well-being. Systematic screening followed by nutrition referral for appropriate interventions is rare. . The purpose of this study was to pilot a screening process followed by nutritional assessment and intervention when warranted for patients with lung malignancies. . Adult patients with lung malignancies were invited to complete the 12-item Anorexia/Cachexia Scale (A/CS-12) on the day of chemotherapy initiation in ambulatory infusion. Those who scored at a preset threshold were referred to nutrition services for a comprehensive assessment and intervention plan. Those who scored better than the threshold completed the A/CS-12 at each infusion visit for as many as 16 weeks. . 90 participants enrolled, and 46 scored in a moderate-to-severe-risk category; of those, 42 were referred to nutrition services.


Pyrophosphorolysis-activatable oligonucleotides may facilitate detection of rare alleles, mutation scanning and analysis of chromatin structures.
Pyrophosphorolysis-activated polymerization (PAP) was initially developed to enhance the specificity of allele-specific PCR for detection of known mutations in the presence of a great excess of wild-type allele. The high specificity of PAP derives from the serial coupling of pyrophosphorolysis-mediated activation of a pyrophosphorolysis-activatable oligonucleotide (P*) followed by extension of the activated oligonucleotide. Herein, we demonstrate that genetically engineered DNA polymerases greatly improve the efficiency of PAP, making it a practical technique for detection of rare mutations. We also show that P* oligonucleotides have the novel and unexpected property of high sensitivity to mismatches throughout at least the 16 3'-terminal nucleotides. Thus, PAP constitutes a technology platform of potential utility whenever high specificity is required along the length of an oligonucleotide.


Implications of a sugar-sweetened beverage (SSB) tax when substitutions to non-beverage items are considered.
Using the 2006 Homescan panel, we estimate the changes in energy, fat and sodium purchases resulting from a tax that increases the price of sugar-sweetened beverages (SSBs) by 20% and the effect of such a tax on body weight. In addition to substitutions that may arise with other beverages, we account for substitutions between SSBs and 12 major food categories. Our main findings are that the tax would result in a decrease in store-bought energy of 24.3kcal per day per person, which would translate into an average weight loss of 1.6 pounds during the first year and a cumulated weight loss of 2.9 pounds in the long run. We do not find evidence of substitution to sugary foods and show that complementary foods could contribute to decreasing energy purchases. Despite their significantly lower price elasticity, the tax has a similar effect on calories for the largest purchasers of SSBs.


The Vaccinia Virus (VACV) B1 and Cellular VRK2 Kinases Promote VACV Replication Factory Formation through Phosphorylation-Dependent Inhibition of VACV B12.
Comparative examination of viral and host protein homologs reveals novel mechanisms governing downstream signaling effectors of both cellular and viral origin. The vaccinia virus B1 protein kinase is involved in promoting multiple facets of the virus life cycle and is a homolog of three conserved cellular enzymes called vaccinia virus-related kinases (VRKs). Recent evidence indicates that B1 and VRK2 mediate a common pathway that is largely uncharacterized but appears independent of previous VRK substrates. Interestingly, separate studies described a novel role for B1 in inhibiting vaccinia virus protein B12, which otherwise impedes an early event in the viral lifecycle. Herein, we characterize the B1/VRK2 signaling axis to better understand their shared functions. First, we demonstrate that vaccinia virus uniquely requires VRK2 for viral replication in the absence of B1, unlike other DNA viruses. Employing loss-of-function analysis, we demonstrate that vaccinia virus's dependence on VRK2 is only observed in the presence of B12, suggesting that B1 and VRK2 share a pathway controlling B12. Moreover, we substantiate a B1/VRK2/B12 signaling axis by examining coprecipitation of B12 by B1 and VRK2. Employing execution point analysis, we reveal that virus replication proceeds normally through early protein translation and uncoating but stalls at replication factory formation in the presence of B12 activity. Finally, structure/function analyses of B1 and VRK2 demonstrate that enzymatic activity is essential for B1 or VRK2 to inhibit B12. Together, these data provide novel insights into B1/VRK signaling coregulation and support a model in which these enzymes modulate B12 in a phosphorylation-dependent manner.IMPORTANCE Constraints placed on viral genome size require that these pathogens must employ sophisticated, yet parsimonious mechanisms to effectively integrate with host cell signaling pathways. Poxviruses are no exception and employ several methods to balance these goals, including encoding single proteins that impact multiple downstream pathways. This study focuses on the vaccinia virus B1 protein kinase, an enzyme that promotes virus replication at multiple phases of the viral lifecycle. Herein, we demonstrate that in addition to its previously characterized functions, B1 inhibits vaccinia virus B12 protein via a phosphorylation-dependent mechanism and that this function of B1 can be complemented by the cellular B1 homolog VRK2. Combined with previous data implicating functional overlap between B1 and an additional cellular B1 homolog, VRK1, these data provide evidence of how poxviruses can be multifaceted in their mimicry of cellular proteins through the consolidation of functions of both VRK1 and VRK2 within the viral B1 protein kinase.


Protective and therapeutic capacity of human single-chain Fv-Fc fusion proteins against West Nile virus.
West Nile virus has spread rapidly across the United States, and there is currently no approved human vaccine or therapy to prevent or treat disease. Passive immunization with antibodies against the envelope protein represents a promising means to provide short-term prophylaxis and treatment for West Nile virus infection. In this study, we identified a panel of 11 unique human single-chain variable region antibody fragments (scFvs) that bind the envelope protein of West Nile virus. Selected scFvs were converted to Fc fusion proteins (scFv-Fcs) and were tested in mice for their ability to prevent lethal West Nile virus infection. Five of these scFv-Fcs, 11, 15, 71, 85, and 95, protected 100% of mice from death when given prior to infection with virus. Two of them, 11 and 15, protected 80% of mice when given at days 1 and 4 after infection. In addition, four of the scFv-Fcs cross-neutralized dengue virus, serotype 2. Binding assays using yeast surface display demonstrated that all of our scFvs bind to sites within domains I and II of West Nile virus envelope protein. These recombinant human scFvs are potential candidates for immunoprophylaxis and therapy of flavivirus infections.


SCALS: a fourth-generation study of assisted living technologies in their organisational, social, political and policy context.
Research to date into assisted living technologies broadly consists of 3 generations: technical design, experimental trials and qualitative studies of the patient experience. We describe a fourth-generation paradigm: studies of assisted living technologies in their organisational, social, political and policy context. Fourth-generation studies are necessarily organic and emergent; they view technology as part of a dynamic, networked and potentially unstable system. They use co-design methods to generate and stabilise local solutions, taking account of context. SCALS (Studies in Co-creating Assisted Living Solutions) consists (currently) of 5 organisational case studies, each an English health or social care organisation striving to introduce technology-supported services to support independent living in people with health and/or social care needs. Treating these cases as complex systems, we seek to explore interdependencies, emergence and conflict. We employ a co-design approach informed by the principles of action research to help participating organisations establish, refine and evaluate their service. To that end, we are conducting in-depth ethnographic studies of people's experience of assisted living technologies (micro level), embedded in evolving organisational case studies that use interviews, ethnography and document analysis (meso level), and exploring the wider national and international context for assisted living technologies and policy (macro level). Data will be analysed using a sociotechnical framework developed from structuration theory. Research ethics approval for the first 4 case studies has been granted. An important outcome will be lessons learned from individual co-design case studies. We will document the studies' credibility and rigour, and assess the transferability of findings to other settings while also recognising unique aspects of the contexts in which they were generated. Academic outputs will include a cross-case analysis and progress in theory and method of fourth-generation assisted living technology research. We will produce practical guidance for organisations, policymakers, designers and service users.


Depression, anxiety, and clinical history in Spanish-speaking American patients with psychogenic nonepileptic seizures (PNES) compared with Spanish-speaking American patients with epilepsy.
The objective of this study was to compare Spanish-speaking American patients with epilepsy to Spanish-speaking American patients with psychogenic nonepileptic seizures (PNES) on depression, anxiety, and other clinical variables. Research on Spanish-speaking American patients with epilepsy or PNES is relatively infrequent, with only a few studies on psychopathology in these two patient groups. Studies of English-speaking patients indicate that those with PNES present with greater depression and anxiety and report poorer quality of life (QOL) when compared with persons with epilepsy (PWEs). Similarly, although psychological trauma is observed in both groups, those with PNES appear to have more traumatic exposure compared with PWEs. This is a retrospective study of 74 Spanish-speaking PWEs (49 women, 31 men) and 34 Spanish-speaking patients with PNES (28 women, 4 men) (2004 to 2017). The diagnosis of epilepsy or PNES was confirmed with video-EEG. Demographic and clinical (psychological trauma, history of psychological treatment, etc.) data were collected, and Spanish versions of the Beck Depression Inventory - second edition (BDI-II) and Beck Anxiety Inventory (BAI) were completed by the patients. Patients with PWEs (M = 18.19, SD = 12.89) differed significantly from those with PNES on a measure of depression (BDI-II, (M = 24.12, SD = 11.20); t (92) = -2.22, p = 0.01). In addition, PWEs (M = 15.76, SD = 14.24) also differed significantly when compared with patients with PNES on a measure of anxiety (BAI, (M = 22.46, SD = 14.02); t (93) = -2.05, p = 0.02). Significant differences in clinical and demographic data were also noted. Spanish-speaking American patients with PNES were significantly more depressed and anxious and reported greater exposure to sexual trauma as compared with PWEs. Furthermore, patients with PNES tended to report more prediagnosis utilization of mental health services than PWEs. After adjusting for potential linear effects of other predictors (e.g., gender, age, seizure frequency, and psychological trauma), only a reported history of psychological trauma had a linear relationship with a depression score while higher seizure frequency and history of mental health treatment had linear relationships with an anxiety score.


Development and evaluation of the US Healthy Food Diversity index.
Varied diets are diverse with respect to diet quality, and existing dietary variety indices do not capture this heterogeneity. We developed and evaluated the multidimensional US Healthy Food Diversity (HFD) index, which measures dietary variety, dietary quality and proportionality according to the 2010 Dietary Guidelines for Americans (DGA). In the present study, two 24 h dietary recalls from the 2003-6 National Health and Nutrition Examination Survey (NHANES) were used to estimate the intake of twenty-six food groups and health weights for each food group were informed by the 2010 DGA. The US HFD index can range between 0 (poor) and 1 - 1/n, where n is the number of foods; the score is maximised by consuming a variety of foods in proportions recommended by the 2010 DGA. Energy-adjusted Pearson's correlations were computed between the US HFD index and each food group and the probability of adequacy for fifteen nutrients. Linear regression was run to test whether the index differentiated between subpopulations with differences in dietary quality commonly reported in the literature. The observed mean index score was 0·36, indicating that participants did not consume a variety of healthful foods. The index positively correlated with nutrient-dense foods including whole grains, fruits, orange vegetables and low-fat dairy (r 0·12 to 0·64) and negatively correlated with added sugars and lean meats (r - 0·14 to - 0·23). The index also positively correlated with the mean probability of nutrient adequacy (r 0·41; P< 0·0001) and identified non-smokers, women and older adults as subpopulations with better dietary qualities. The US HFD index may be used to inform national dietary guidance and investigate whether healthful dietary variety promotes weight control.


Visualization of protein interaction networks: problems and solutions.
Visualization concerns the representation of data visually and is an important task in scientific research. Protein-protein interactions (PPI) are discovered using either wet lab techniques, such mass spectrometry, or in silico predictions tools, resulting in large collections of interactions stored in specialized databases. The set of all interactions of an organism forms a protein-protein interaction network (PIN) and is an important tool for studying the behaviour of the cell machinery. Since graphic representation of PINs may highlight important substructures, e.g. protein complexes, visualization is more and more used to study the underlying graph structure of PINs. Although graphs are well known data structures, there are different open problems regarding PINs visualization: the high number of nodes and connections, the heterogeneity of nodes (proteins) and edges (interactions), the possibility to annotate proteins and interactions with biological information extracted by ontologies (e.g. Gene Ontology) that enriches the PINs with semantic information, but complicates their visualization. In these last years many software tools for the visualization of PINs have been developed. Initially thought for visualization only, some of them have been successively enriched with new functions for PPI data management and PIN analysis. The paper analyzes the main software tools for PINs visualization considering four main criteria: (i) technology, i.e. availability/license of the software and supported OS (Operating System) platforms; (ii) interoperability, i.e. ability to import/export networks in various formats, ability to export data in a graphic format, extensibility of the system, e.g. through plug-ins; (iii) visualization, i.e. supported layout and rendering algorithms and availability of parallel implementation; (iv) analysis, i.e. availability of network analysis functions, such as clustering or mining of the graph, and the possibility to interact with external databases. Currently, many tools are available and it is not easy for the users choosing one of them. Some tools offer sophisticated 2D and 3D network visualization making available many layout algorithms, others tools are more data-oriented and support integration of interaction data coming from different sources and data annotation. Finally, some specialistic tools are dedicated to the analysis of pathways and cellular processes and are oriented toward systems biology studies, where the dynamic aspects of the processes being studied are central. A current trend is the deployment of open, extensible visualization tools (e.g. Cytoscape), that may be incrementally enriched by the interactomics community with novel and more powerful functions for PIN analysis, through the development of plug-ins. On the other hand, another emerging trend regards the efficient and parallel implementation of the visualization engine that may provide high interactivity and near real-time response time, as in NAViGaTOR. From a technological point of view, open-source, free and extensible tools, like Cytoscape, guarantee a long term sustainability due to the largeness of the developers and users communities, and provide a great flexibility since new functions are continuously added by the developer community through new plug-ins, but the emerging parallel, often closed-source tools like NAViGaTOR, can offer near real-time response time also in the analysis of very huge PINs.


Elastic Functional Coding of Riemannian Trajectories.
Visual observations of dynamic phenomena, such as human actions, are often represented as sequences of smoothly-varying features. In cases where the feature spaces can be structured as Riemannian manifolds, the corresponding representations become trajectories on manifolds. Analysis of these trajectories is challenging due to non-linearity of underlying spaces and high-dimensionality of trajectories. In vision problems, given the nature of physical systems involved, these phenomena are better characterized on a low-dimensional manifold compared to the space of Riemannian trajectories. For instance, if one does not impose physical constraints of the human body, in data involving human action analysis, the resulting representation space will have highly redundant features. Learning an effective, low-dimensional embedding for action representations will have a huge impact in the areas of search and retrieval, visualization, learning, and recognition. Traditional manifold learning addresses this problem for static points in the euclidean space, but its extension to Riemannian trajectories is non-trivial and remains unexplored. The difficulty lies in inherent non-linearity of the domain and temporal variability of actions that can distort any traditional metric between trajectories. To overcome these issues, we use the framework based on transported square-root velocity fields (TSRVF); this framework has several desirable properties, including a rate-invariant metric and vector space representations. We propose to learn an embedding such that each action trajectory is mapped to a single point in a low-dimensional euclidean space, and the trajectories that differ only in temporal rates map to the same point. We utilize the TSRVF representation, and accompanying statistical summaries of Riemannian trajectories, to extend existing coding methods such as PCA, KSVD and Label Consistent KSVD to Riemannian trajectories or more generally to Riemannian functions. We show that such coding efficiently captures trajectories in applications such as action recognition, stroke rehabilitation, visual speech recognition, clustering and diverse sequence sampling. Using this framework, we obtain state-of-the-art recognition results, while reducing the dimensionality/ complexity by a factor of 100-250x. Since these mappings and codes are invertible, they can also be used to interactively-visualize Riemannian trajectories and synthesize actions.


Hepatoma cell density promotes claudin-1 and scavenger receptor BI expression and hepatitis C virus internalization.
Hepatitis C virus (HCV) entry occurs via a pH- and clathrin-dependent endocytic pathway and requires a number of cellular factors, including CD81, the tight-junction proteins claudin 1 (CLDN1) and occludin, and scavenger receptor class B member I (SR-BI). HCV tropism is restricted to the liver, where hepatocytes are tightly packed. Here, we demonstrate that SR-BI and CLDN1 expression is modulated in confluent human hepatoma cells, with both receptors being enriched at cell-cell junctions. Cellular contact increased HCV pseudoparticle (HCVpp) and HCV particle (HCVcc) infection and accelerated the internalization of cell-bound HCVcc, suggesting that the cell contact modulation of receptor levels may facilitate the assembly of receptor complexes required for virus internalization. CLDN1 overexpression in subconfluent cells was unable to recapitulate this effect, whereas increased SR-BI expression enhanced HCVpp entry and HCVcc internalization, demonstrating a rate-limiting role for SR-BI in HCV internalization.


The scope and limits of conscientious objection.
Principles of religious freedom protect physicians, nurses and others who refuse participation in medical procedures to which they hold conscientious objections. However, they cannot decline participation in procedures to save life or continuing health. Physicians who refuse to perform procedures on religious grounds must refer their patients to non-objecting practitioners. When physicians refuse to accept applicants as patients for procedures to which they object, governmental healthcare administrators must ensure that non-objecting providers are reasonably accessible. Nurses' conscientious objections to participate directly in procedures they find religiously offensive should be accommodated, but nurses cannot object to giving patients indirect aid. Medical and nursing students cannot object to be educated about procedures in which they would not participate, but may object to having to perform them under supervision. Hospitals cannot usually claim an institutional conscientious objection, nor discriminate against potential staff applicants who would not object to participation in particular procedures.


Nineteen additional unpredicted transcripts from human chromosome 21.
The identification of all human chromosome 21 (HC21) genes is a necessary step in understanding the molecular pathogenesis of trisomy 21 (Down syndrome). The first analysis of the sequence of 21q included 127 previously characterized genes and predicted an additional 98 novel anonymous genes. Recently we evaluated the quality of this annotation by characterizing a set of HC21 open reading frames (C21orfs) identified by mapping spliced expressed sequence tags (ESTs) and predicted genes (PREDs), identified only in silico. This study underscored the limitations of in silico-only gene prediction, as many PREDs were incorrectly predicted. To refine the HC21 annotation, we have developed a reliable algorithm to extract and stringently map sequences that contain bona fide 3' transcript ends to the genome. We then created a specific 21q graphical display allowing an integrated view of the data that incorporates new ESTs as well as features such as CpG islands, repeats, and gene predictions. Using these tools we identified 27 new putative genes. To validate these, we sequenced previously cloned cDNAs and carried out RT-PCR, 5'- and 3'-RACE procedures, and comparative mapping. These approaches substantiated 19 new transcripts, thus increasing the HC21 gene count by 9.5%. These transcripts were likely not previously identified because they are small and encode small proteins. We also identified four transcriptional units that are spliced but contain no obvious open reading frame. The HC21 data presented here further emphasize that current gene prediction algorithms miss a substantial number of transcripts that nevertheless can be identified using a combination of experimental approaches and multiple refined algorithms.


Circadian rhythms in the synthesis and degradation of a master clock protein KaiC in cyanobacteria.
A circadian rhythm in the accumulation of the core clock protein KaiC has been proposed to be important for proper circadian timing in the cyanobacterium Synechococcus elongatus PCC 7942 under continuous light conditions. Cycling in the abundance of the KaiC protein is delayed to the rhythm of its mRNA by approximately 8 h, consistent with the proposed function of KaiC as a negative feedback regulator of kaiBC transcription. Here, we present temporal profiles of the synthesis and degradation of KaiC protein that determine the rhythm of its accumulation. The rate of KaiC synthesis shows a robust circadian oscillation, which is delayed to the mRNA rhythm slightly and advances the rhythm of KaiC accumulation by approximately 6 h. The stability of KaiC protein also shows circadian fluctuations, such that KaiC degradation is suppressed during the mid-subjective night. These results suggest that transcriptional, translational, and posttranslational processes are important for the proper circadian changes in KaiC accumulation. Moreover, the turnovers of the phosphorylated and non-phosphorylated forms of KaiC show robust circadian rhythms with an anti-phase relationship to each other. Interestingly, when translation was inhibited, KaiC degradation and phosphorylation proceeded within at least 4 h in a circadian phase-dependent manner. Thus, the circadian timing seems flexible even when any perturbation in protein synthesis occurs.


Olig3 is not involved in the ventral patterning of spinal cord.
At embryonic stages, Olig3 is initially expressed in the dorsal-most region of the spinal cord, but later in the ventral marginal zone as well. Previous studies indicated that Olig3 controlled the patterning of dorsal spinal cord and loss of Olig3 function led to the re-specification of dI2 and dI3 neurons into dI4 interneurons. However, the role of Olig3 in regulating the development of ventral spinal cord has remained unknown. BrdU labeling demonstrated that ventral Olig3 was expressed in the post-mitotic neurons and Olig3+ cells seen at late embryonic stages were born at the earlier stage but remained in the marginal zone throughout embryogenesis. Loss-of-function and gain-of-function experiment indicated that Nkx2.2 regulated the expression of Olig3 in V3 interneurons. However, Olig3 mutation didn't apparently affect the generation and migration of ventral neurons. These findings suggest that Olig3 plays different roles in regulating the development of dorsal and ventral spinal cord.


Assessing of policies and practices for occupational exposure to blood-borne viral infections in Tanta University Hospitals, Egypt.
One of the best ways to investigate and improve the effectiveness of polices for prevention and control of infections is through systematic and rigorous evaluation of the structural, functional, and practical elements of these polices. To assess the policies for managing occupational exposure to blood-borne viral infections in Tanta University Hospitals. A cross-sectional survey was carried out. A checklist was used to collect data related to the hospital policy regarding occupational exposure to blood-borne viral infections which was filled by direct personal interviews with the members of infection control (IC) committee of Tanta University Hospitals where the percentage of those in compliance with specific occupational management policies were reported. All studied participants reported lack of access to written infection control manual and only 14.3 % reported that infection control policies and procedures are updated yearly. Only 32.5 % of studied healthcare workers (HCWs) were not aware by the availability of a needle injury clinic. Only 28.6 % of the members of IC committee reported that pre-placement screening of HCWs for baseline blood tests for HBV, HCV, or HIV was conducted; however, periodic screening for these infections was not conducted as reported by all of the members. Among the members of IC committee, 57.1 % recorded availability of post-exposure evaluation. Only 42.8 % of the members of IC committee reported ensuring HCWs' confidentiality when reporting their exposure incidents. Both exposure management policies and practices were not aligning with the national guidelines.


Climate warming accelerates temporal scaling of grassland soil microbial biodiversity.
Determining the temporal scaling of biodiversity, typically described as species-time relationships (STRs), in the face of global climate change is a central issue in ecology because it is fundamental to biodiversity preservation and ecosystem management. However, whether and how climate change affects microbial STRs remains unclear, mainly due to the scarcity of long-term experimental data. Here, we examine the STRs and phylogenetic-time relationships (PTRs) of soil bacteria and fungi in a long-term multifactorial global change experiment with warming (+3 °C), half precipitation (-50%), double precipitation (+100%) and clipping (annual plant biomass removal). Soil bacteria and fungi all exhibited strong STRs and PTRs across the 12 experimental conditions. Strikingly, warming accelerated the bacterial and fungal STR and PTR exponents (that is, the w values), yielding significantly (P < 0.001) higher temporal scaling rates. While the STRs and PTRs were significantly shifted by altered precipitation, clipping and their combinations, warming played the predominant role. In addition, comparison with the previous literature revealed that soil bacteria and fungi had considerably higher overall temporal scaling rates (w = 0.39-0.64) than those of plants and animals (w = 0.21-0.38). Our results on warming-enhanced temporal scaling of microbial biodiversity suggest that the strategies of soil biodiversity preservation and ecosystem management may need to be adjusted in a warmer world.


Krüpple-like factor 5 is essential for mammary gland development and tumorigenesis.
Krüpple-like factor 5 (KLF5) is required for the development of the embryo and multiple organs, such as the lung and intestine. KLF5 plays a pro-proliferative and oncogenic role in several carcinomas, including breast cancer. However, its role in normal mammary gland development and oncogenesis has not been elucidated in vivo. In this study, we used mammary gland-specific Klf5 conditional knockout mice derived by mating Klf5-LoxP and MMTV-Cre mice. The genetic ablation of Klf5 suppresses mammary gland ductal elongation and lobuloalveolar formation. Klf5 deficiency inhibits mammary epithelial cell proliferation, survival, and stem cell maintenance. Klf5 promotes mammary stemness, at least partially, by directly promoting the transcription of Slug. Finally, Klf5 depletion suppressed PyMT-induced mammary gland tumor cell stemness, tumor initiation, and growth in vivo. Slug also mediated these functions of Klf5 in vivo. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


The Ukrainian-American study of leukemia and related disorders among Chornobyl cleanup workers from Ukraine: III. Radiation risks.
Leukemia is one of the cancers most susceptible to induction by ionizing radiation, but the effects of lower doses delivered over time have not been quantified adequately. After the Chornobyl (Chernobyl) accident in Ukraine in April 1986, several hundred thousand workers who were involved in cleaning up the site and its surroundings received fractionated exposure, primarily from external gamma radiation. To increase our understanding of the role of protracted low-dose radiation exposure in the etiology of leukemia, we conducted a nested case-control study of leukemia in a cohort of cleanup workers identified from the Chornobyl State Registry of Ukraine. The analysis is based on 71 cases of histologically confirmed leukemia diagnosed in 1986-2000 and 501 age- and residence-matched controls selected from the same cohort. Study subjects or their proxies were interviewed about their cleanup activities and other relevant factors. Individual bone marrow radiation doses were estimated by the RADRUE dose reconstruction method (mean dose = 76.4 mGy, SD = 213.4). We used conditional logistic regression to estimate leukemia risks. The excess relative risk (ERR) of total leukemia was 3.44 per Gy [95% confidence interval (CI) 0.47-9.78, P < 0.01]. The dose response was linear and did not differ significantly by calendar period of first work in the 30-km Chornobyl zone, duration or type of work. We found a similar dose-response relationship for chronic and non-chronic lymphocytic leukemia [ERR = 4.09 per Gy (95% CI < 0-14.41) and 2.73 per Gy (95% CI < 0-13.50), respectively]. To further clarify these issues, we are extending the case-control study to ascertain cases for another 6 years (2001-2006).


Articulatory placement for /t/, /d/, /k/ and /g/ targets in school age children with speech disorders associated with cleft palate.
This study used electropalatography (EPG) to identify place of articulation for lingual plosive targets /t/, /d/, /k/ and /g/ in the speech of 15 school age children with repaired cleft palate. Perceptual judgements indicated that all children had correct velar placement for /k/, /g/ targets, but /t/, /d/ targets were produced as errors involving palatalization or velar placement. An EPG classification scheme identified alveolar, palatal and velar placement. Articulations involving contact in alveolar and velar regions simultaneously were identified as alveolar velar double articulations (AVDAs). The classification revealed that AVDAs were relatively frequent, with 28% of alveolar and 12% of velar targets affected, and ten out of the 15 children produced one or more of these abnormal articulations. The majority of children had variable placements, with alveolar more variable than velar targets. The positive finding from the EPG data revealed that most children with perceptual errors for /t/, /d/ were able to make closure in the alveolar region during at least some of their attempts to articulate these targets. It is argued that appropriate analysis and interpretation of EPG data provide clinically relevant information about tongue placement in cleft palate speech.


Pdx1 regulates pancreas tubulogenesis and E-cadherin expression.
Current efforts in developing treatments for diabetes focus on in vitro generation of functional β-cells for cell replacement therapies; however, these attempts have only been partly successful because factors involved in islet formation remain incompletely understood. The embryonic pancreas, which gives rise to β-cells, undergoes early epithelial rearrangements, including transient stratification of an initially monolayered epithelium, followed by microlumen formation and later resolution into branches. Within the epithelium, a multipotent progenitor cell (MPC) population is specified, giving rise to three important lineages: acinar, ductal and endocrine. Pdx1 is a transcription factor required for pancreas development and lineage specification; however, few Pdx1 targets that regulate pancreatogenesis have been identified. We find that pancreatic defects in Pdx1(-/-) embryos initiate at the time when the progenitor pool is specified and the epithelium should resolve into branches. Pdx1(-/-) microlumen diameters expand aberrantly, resulting in failure of epithelial tubulogenesis and ductal plexus formation. Pdx1(-/-) epithelial cell proliferation is decreased and the MPC pool is rapidly lost. We identify two conserved Pdx1 binding sites in the epithelial cadherin (E-cad, Cdh1) promoter, and show that Pdx1 directly binds and activates E-cad transcription. In addition, Pdx1 is required in vivo for maintenance of E-cad expression, actomyosin complex activity and cell shape. These findings demonstrate a novel link between regulators of epithelial architecture, specification of pancreatic cell fate and organogenesis.


Commercial molecular panels are of limited utility in the classification of pancreatic cystic lesions.
The PathfinderTG biomarker panel is useful in the evaluation of pancreatic cysts that have clinical features suspicious for malignancy, but its utility in classifying fine-needle aspiration biopsies from small pancreatic cystic lesions is yet to be proven. We used morphology to classify 20 pancreatic cyst cytology aspirates, all of which met radiographic criteria for close observation. Cases were cytologically classified as consistent with pseudocyst, serous cystadenoma, or mucinous neoplasm with low-grade, intermediate-grade, or high-grade dysplasia and analyzed for carcinoembryonic antigen. Redpath Integrated Pathology Inc. rendered diagnoses of nonmucinous (reactive/indolent or serous) or mucinous (low-risk or at risk) cyst on the basis of results of the PathfinderTG panel (KRAS mutations, DNA content, and loss of heterozygosity at microsatellites linked to tumor suppressor genes). Cytologic and commercial laboratory diagnoses were concordant in only 7 (35%) cases. Seven cysts classified as mucinous with low-grade dysplasia by cytology were interpreted as nonmucinous on the basis of the PathfinderTG panel, 2 of which were resected mucinous cysts. Two pancreatitis-related pseudocysts were misdiagnosed as low-risk mucinous cysts; 1 mucinous cyst with low-grade dysplasia was considered at risk for neoplastic progression using the PathfinderTG panel. Only 1 cyst misclassified as pseudocyst by cytology, but low-risk mucinous cyst by molecular analysis, proved to be a mucinous cystic neoplasm with low-grade dysplasia after surgical resection. We conclude that the PathfinderTG panel may aid the classification of pancreatic lesions, but is often inaccurate and should not replace cytologic evaluation of these lesions.


Role of lungs and inactive muscle in acid-base control after maximal exercise.
The pulmonary responses and changes in plasma acid-base status occurring across the inactive forearm muscle were examined after 30 s of intense exercise in six male subjects exercising on an isokinetic cycle ergometer. Arterial and deep forearm venous blood were sampled at rest and during 10 min after exercise; ventilation and pulmonary gas exchange variables were measured breath by breath during exercise and recovery. Immediately after exercise, ventilation and CO2 output increased to 124 +/- 17 1/min and 3.24 +/- 0.195 l/min, respectively. The subsequent decrease in CO2 output was slower than the decrease in O2 intake (half time of 105 +/- 15 and 47 +/- 4 s, respectively); the respiratory exchange ratio was greater than 1.0 throughout the 10 min of recovery. Arterial plasma concentrations of Na+, K+, and Ca2+ increased transiently after exercise. Arterial lactate ion concentration ([La-]) increased to 14-15 meq/l within 1.5 min and remained at this level for the rest of the study. Throughout recovery there was a positive arteriovenous [La-] difference of 4-5 meq/l, associated with an increase in the arteriovenous strong ion difference ([SID]) and by a large increase in the venous Pco2 and [HCO3-]. These findings were interpreted as indicating uptake of La- by the inactive muscle, leading to a fall in the muscle [SID] and increase in plasma [SID], associated with an increase in muscle PCO2. The venoarterial CO2 content difference was 38% greater than could be accounted for by metabolism of La- alone, suggesting liberation of CO2 stored in muscle, possibly as carbamate.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population.
To characterise the epidemiological features of chronic inflammatory demyelinating polyneuropathy (CIDP) in the Japanese population, this study performed a nationwide assessment of the prevalence and incidence rates in Japan. The prevalence rate per 100 000 was 1.61 in the total population; 2.01 in males and 1.23 in females. The age dependent prevalence rates were 0.23 in juveniles (<15 years old), 1.50 in young adults (15-55 years) and 2.31 in elderly adults (>55 years). The sex and age dependent prevalence rates were 0.22 in males and 0.24 in females in juveniles, 1.81 in males and 1.19 in females in young adults, and 3.12 in males and 1.64 in females in elderly adults. The annual incidence rate per 100 000 was 0.48 in the total population, 0.58 in males and 0.38 in females. The age dependent incidence rate was 0.06 in juveniles, 0.40 in young adults and 0.73 in elderly adults. The sex and age dependent incidence rate was 0.05 in males and 0.08 in females in juveniles, 0.50 in males and 0.30 in females in young adults, and 0.93 in males and 0.58 in females in elderly adults. Both the prevalence and incidence rates were very similar throughout the eight geographical areas studied, from the northern to the southern parts of Japan. The prevalence and incidence rates were similar to those reported in the Caucasian population. The pathogenic background is suggested to be common throughout the different races and geographic areas, while gender and age effects should be taken into account in the pathogenesis of CIDP.


Off-label medicine use: Ethics, practice and future directions.
Medicine use is considered off-label when used for an indication, at a dose, via a route of administration or in a patient group not included in the approved product information. Off-label use varies according to therapeutic class and patient group, and often occurs in those who are vulnerable. The aim of this article is to discuss ethical, practice and policy considerations associated with off-label medicine use. A number of professional organisations have issued guidance in relation to off-label medicine use. Prescribers should inform patients and document consent when prescribing off-label, including an open discussion about known and unknown benefits and risks. It is important that the prescriber documents the reason for off-label use in the patient's record and ensures that patients are aware of the intended duration and relevant monitoring. Australia's new national health priority of Quality Use of Medicine and Medicine Safety should stimulate all stakeholders including consumers to work together to address off-label medicine use.


Reduction in the incidence of influenza A but not influenza B associated with use of hand sanitizer and cough hygiene in schools: a randomized controlled trial.
Laboratory-based evidence is lacking regarding the efficacy of nonpharmaceutical interventions (NPIs) such as alcohol-based hand sanitizer and respiratory hygiene to reduce the spread of influenza. The Pittsburgh Influenza Prevention Project was a cluster-randomized trial conducted in 10 elementary schools in Pittsburgh, PA, during the 2007 to 2008 influenza season. Children in 5 intervention schools received training in hand and respiratory hygiene, and were provided and encouraged to use hand sanitizer regularly. Children in 5 schools acted as controls. Children with influenza-like illness were tested for influenza A and B by reverse-transcriptase polymerase chain reaction. A total of 3360 children participated in this study. Using reverse-transcriptase polymerase chain reaction, 54 cases of influenza A and 50 cases of influenza B were detected. We found no significant effect of the intervention on the primary study outcome of all laboratory-confirmed influenza cases (incidence rate ratio [IRR]: 0.81; 95% confidence interval [CI]: 0.54, 1.23). However, we did find statistically significant differences in protocol-specified ancillary outcomes. Children in intervention schools had significantly fewer laboratory-confirmed influenza A infections than children in control schools, with an adjusted IRR of 0.48 (95% CI: 0.26, 0.87). Total absent episodes were also significantly lower among the intervention group than among the control group; adjusted IRR 0.74 (95% CI: 0.56, 0.97). NPIs (respiratory hygiene education and the regular use of hand sanitizer) did not reduce total laboratory-confirmed influenza. However, the interventions did reduce school total absence episodes by 26% and laboratory-confirmed influenza A infections by 52%. Our results suggest that NPIs can be an important adjunct to influenza vaccination programs to reduce the number of influenza A infections among children.


Assessments of Stress of Conscience, Perceptions of Conscience, Burnout, and Social Support Before and After Implementation of a Participatory Action-Research-Based Intervention.
Interventions aiming to constructively address stress of conscience are rare. The aim of the study was to compare assessments of stress of conscience, perceptions of conscience, burnout, and social support among health care personnel (HCP) working in municipal residential care of older adults, before and after participation in a participatory action research (PAR) intervention aiming to learn to constructively deal with troubled conscience. Questionnaire data were collected at baseline and at follow-up (1-year interval; n = 29). Descriptive statistics and nonparametric statistical tests were used to make comparisons between baseline and follow-up. HCP gave significantly higher scores to the question, "Are your work achievements appreciated by your immediate superior?" at follow-up compared with baseline. No significant differences in levels of stress of conscience and burnout at follow-up were found. The results suggested that a PAR intervention aiming to learn HCP to deal with their troubled conscience in difficult situations could be partially successful.


The epidemiology of snake bite in Central Province and National Capital District, Papua New Guinea.
Snake bite is an important medical problem in some areas of Papua New Guinea and appears to be most common in the Central Province and National Capital District. The overall incidence for Central Province is 215.5 per 100,000 population, but Kairuku subprovince has an incidence of 526 per 100,000, which is amongst the highest in the world. The clinical pattern of envenoming also varies within the Province, suggesting that different species of snake may be responsible for bites in different areas. Most envenomed patients are bitten during daylight on the lower limb and are rarely able to describe the snake. The mortality rate in Central Province is 7.9 per 100,000; most patients die from ventilatory failure due to severe neurotoxicity. Mortality might be reduced by increased use of compression bandaging as a first aid measure, earlier treatment with antivenom and earlier referral to hospital.


Comparison of trans-cortical and cancellous screws to press fit for acetabular shell fixation in total hip arthroplasty: A cadaveric study.
Total hip arthroplasty complications are associated with mechanical loosening of the acetabular component, which may be attributed to the type of fixation used (press fit, trans-cortical screws, cancellous screws). Therefore, the purpose of this study was to compare trans-cortical and cancellous screws to press fit for fixation of the acetabular shell. Five cadaveric pelvis specimens were hemisected (N = 10) at the sacroiliac joint. Each hemi-pelvis was initially tested with a press fit cup followed by the left and right pairs being randomized to either a cancellous or trans-cortical screw condition. Each fixation was tested by applying a load to a rod inserted into the centre of the acetabular cup at 0.5 mm/s, until failure occurred. The failure force, failure moment, and the rotation angle of the cup at failure were calculated. The cups fixated with a trans-cortical screw failed at a significantly greater mean [SD] force (1046.20 [386.52] N). The trans-cortical screws also significantly increased the angle of failure 46.29 (16.90) ° compared to the press-fit cups (6.73 [4.59] °). Finally, there was a significant increase in the failure moment, such that, the trans-cortical condition failed at a mean (SD) moment of 53.75 (16.24) Nm compared to 9.59 (1.85) Nm and 32.15 (18.16) Nm for the press fit and cancellous (p = 0.044) conditions, respectively. The acetabular shells that were fixated with trans-cortical screws provide greater stability compared to the press-fit cups or cancellous screws.


A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors.
Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors.Experimental Design: A standard 3 + 3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma.Results: Of the 74 patients enrolled, the most common malignancies were non-small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across five dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug-drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed downregulation of genes in the insulin-like growth factor receptor 1 pathway.Conclusions: Dacomitinib-figitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor adenoid cystic carcinoma. Clin Cancer Res; 23(5); 1177-85. ©2016 AACRSee related commentary by Sundar et al., p. 1123.


Genetic contribution to radiographic severity in osteoarthritis of the knee.
Knee osteoarthritis (OA) has a significant genetic component. The authors have assessed the role of three variants reported to influence risk of knee OA with p<5×10-8 in determining patellofemoral and tibiofemoral Kellgren Lawrence (K/L) grade in knee OA cases. 3474 knee OA cases with sky-line and weight-bearing antero-posterior x-rays of the knee were selected based on the presentation of K/L grade ≥2 at either the tibiofemoral or patellofemoral compartments for one or both knees. Patients belonging to three UK cohorts, were genotyped for rs143383, rs4730250 and rs11842874 mapping to the GDF5, COG5 and MCF2L genes, respectively. The association between tibiofemoral K/L grade and patellofemoral K/L grade was assessed after adjusting for age, gender and body mass index. No significant association was found between the rs4730250 and radiographic severity. The rs11842874 mapping to MCF2L was found to be nominally significantly associated with patellofemoral K/L grade as a quantitative trait (p=0.027) but not as a binary trait. The GDF5 single nucleotide polymorphism rs143383 was associated with tibiofemoral K/L grade (β=0.05 (95% CI 0.02 to 0.08) p=0.0011). Our data indicate that within individuals affected by radiographic knee OA, OAGDF5 has a modest but significant effect on radiographic severity after adjustment for the major risk factors.


Is socioeconomic status associated with utilization of health care services in a single-payer universal health care system?
To assess an association of Socio-economic status with utilization of health care services between years 2002 and 2008 in Israel. We retrospectively analyzed the utilization of health care services in a cohort of 100,000 members, 21 years and older, of a Clalit Health Services. The research compared utilization according to the neighborhood SES status; and clinic's location as another SES proxy. Data included: Charlson Score morbidity factor, utilization of health care services (visits to primary physicians and specialists, purchase of pharmaceuticals, number of hospitalization days, visits to ED, utilization of laboratory tests and imaging). The analysis was performed using Generalized Linear Model (GLM) technique. People with lower SES visited more the ED and primary physicians and were hospitalized for longer periods. People with higher SES visited more specialists, bought more prescription drugs and used more medical imaging. The associations between SES and most of the services we analyzed did not change between 2002 and 2008. However, the gap between lower and higher SES levels in ED visits and the use of prescription drugs slightly increased over time, while the gap in visits to specialists decreased. The research shows that even in a universal health care system SES is associated with utilization of health care services. In order to improve equity in utilization of services the Israeli public health should reduce economic barriers and in parallel invest in making information accessible to improve "navigation skills" for all.


Aging and dependence in Brazil: sociodemographic and care characteristics of older adults and caregivers.
This paper aims to identify sociodemographic and care characteristics of dependent older adults, formal and family caregivers in municipalities from different Brazilian regions. A cross-sectional study was carried out with a sample of 175 people, of whom 64 were older adults, 27 formal caregivers, and 84 family caregivers. Semi-structured interviews were conducted with specific questions for each group on the theme of care and dependence. Most older adults were female, aged 80 years or older, with low education and have been dependent for four years or more. Older adults reported feelings of loneliness, pointed out difficulties in medical care, and 29% had only access to Primary Health Care actions. Inequalities, burden, illnesses, and social problems were found among family caregivers. Black females with no formal employment, little or no training for the function, and low remuneration predominated among formal caregivers, and care was associated with domestic chores. We can conclude that gender and race inequalities persist in the care of dependent older adults, and we observed that the rigid social roles assigned to men and women in Brazil persist in the family and work dynamics in caring for the dependent older adults.


Liver histology in hepatitis C infection: a comparison between patients with persistently normal or abnormal transaminases.
Forty two cases of confirmed hepatitis C virus (HCV) infection with available liver histology were studied. Most patients, 23 of 42 (55%) had abnormal liver function tests but 19 of 42 (45%) had persistently normal liver transaminases (mean aspartate transaminase (AST) 24.1 IU/l, mean follow up 10 months). Histological examinations in the group with normal AST activities were normal in two of 19 (11%), showed non-specific reactive hepatitis in eight of 19 (42%), chronic persistent hepatitis in six of 19 (31%), and chronic active hepatitis in three of 19 (16%). Twenty three of 42 (55%) had either persistently or temporary raised liver transaminases (mean AST 96.2 IU/l, mean follow up 16 months). Histological examinations in this second group with abnormal liver biochemistry showed reactive hepatitis in five of 23 (22%), chronic persistent hepatitis in six of 23 (26%), chronic active hepatitis in 10 of 23 (43%), and cirrhosis in two (9%). Average alcohol intake was significantly higher in the group within abnormal liver function (17.8 v 6.4 units, p = 0.01). Although serious pathology was more frequent in the abnormal transaminase group, significant liver pathology (chronic persistent hepatitis or chronic active hepatitis) was found in nine of 19 (47%) of cases with repeatedly normal transaminases. Liver biopsy is advised in all cases of chronic hepatitis C infection to accurately assess both the degree of fibrosis and the current activity of the disease.


Identification of compartment- and process-specific molecules required for "synaptic tagging" during long-term potentiation and long-term depression in hippocampal CA1.
Protein synthesis-dependent forms of hippocampal long-term potentiation (late LTP) and long-term depression (late LTD) are prominent cellular mechanisms underlying memory formation. Recent data support the hypothesis that neurons store relevant information in dendritic functional compartments during late LTP and late LTD rather than in single synapses. It has been suggested that processes of "synaptic tagging" are restricted to such functional compartments. Here, we show that in addition to apical CA1 dendrites, synaptic tagging also takes place within basal CA1 dendritic compartments after LTP induction. We present data that tagging in the basal dendrites is restricted to these compartments. Plasticity-related proteins, partially nonspecific to the locally induced process, are synthesized in dendritic compartments and then captured by local, process-specific synaptic tags. We support these findings in two ways: (1) late LTP/LTD, locally induced in apical or basal (late LTP) dendrites of hippocampal CA1 neurons, does not spread to the basal or apical compartment, respectively; (2) the specificity of the synaptic plasticity event is achieved by the activation of process- and compartment-specific synaptic tag molecules. We have identified calcium/calmodulin-dependent protein kinase II as the first LTP-specific and extracellular signal-regulated kinase 1/2 as LTD-specific tag molecules in apical dendritic CA1 compartments, whereas either protein kinase A or protein kinase Mzeta mediates LTP-specific tags in basal dendrites.


Renal Damage Frequency in Patients with Solitary Kidney and Factors That Affect Progression.
Background. The aim of this study is to assess renal damage incidence in patients with solitary kidney and to detect factors associated with progression. Methods. Medical records of 75 patients with solitary kidney were investigated retrospectively and divided into two groups: unilateral nephrectomy (group 1) and unilateral renal agenesis/dysplasia (group 2). According to the presence of kidney damage, each group was divided into two subgroups: group 1a/b and group 2a/b. Results. Patients in group 1 were older than those in group 2 (p = 0.001). 34 patients who comprise group 1a had smaller kidney size (p = 0.002) and higher uric acid levels (p = 0.028) than those in group 1b at presentation. Uric acid levels at first and last visit were associated with renal damage progression (p = 0.004, 0.019). 18 patients who comprise group 2a were compared with those in group 2b in terms of presence of DM (p = 0.038), HT (p = 0.003), baseline proteinuria (p = 0.014), and uric acid (p = 0.032) levels and group 2a showed higher rates for each. Progression was more common in patients with DM (p = 0.039), HT (p = 0.003), higher initial and final visit proteinuria (p = 0.014, for both), and higher baseline uric acid levels (p = 0.047). Conclusions. The majority of patients with solitary kidney showed renal damage at presentation. Increased uric acid level is a risk factor for renal damage and progression. For early diagnosis of renal damage and reducing the risk of progression, patients should be referred to a nephrologist as early as possible.


Altered gastric chief cell lineage differentiation in histamine-deficient mice.
The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.


Adaptation and validation of a short French version of the Drive for Muscularity Scale in male athletes (DMS-FR).
The purpose of this paper was to adapt and examine the psychometric properties of a French-language Drive for Muscularity Scale (DMS). First, a preliminary version of the scale, based on both the English-language version of the DMS and the literature on the drive for muscularity, was developed following a committee validation process. Second, the factor structure of the DMS-FR was investigated with principal component analysis (PCA) in a sample of 114 male athletes (Mage = 23.35; SDage = 4.93), leading to a nine-item scale (Study 1). Third, in Study 2, the internal factor structure, temporal stability, and concurrent validity were examined through a series of structural hypothetical modelisation in a sample of 129 male athletes (Mage = 27.03; SDage = 7.81). The results indicated that the scale has good psychometric properties. Specifically, the PCA, and the series of structural hypothetical modelisation, suggested two theoretical factors (i.e., Muscularity Body Dissatisfaction and Muscularity Behaviors), and more, with a bi-factor model in a SEM. The results also indicated sufficient concurrent validity with the Male Body Dissatisfaction Scale (MBDS) and adequate internal consistency (Cronbach's alphas were .87 for the Muscularity Body Dissatisfaction subscale, and .88 for the Muscularity Behaviors subscale). The findings overall suggest good reliability and construct validity for this French version of the DMS (DMS-FR), which will be useful for future research and clinical practice in French-speaking countries.


The safety of ONRAB® in select non-target wildlife.
ONRAB(®) is a recombinant human adenovirus type 5 (HAd5) with the rabies glycoprotein gene incorporated into its genome. ONRAB(®) has been used in Canada as an oral rabies vaccine in target wildlife species such as: red fox (Vulpes vulpes), raccoon (Procyon lotor), and striped skunk (Mepthis mephitis). We evaluated the safety of ONRAB(®) in non-target wildlife species likely to contact the vaccine baits during oral rabies vaccine campaigns in the United States. We investigated the effects of oral inoculation of high titer ONRAB(®), approximately ten times the dose given to target species, in wood rats (Neotoma spp.), eastern cottontail rabbits (Sylvilagus floridanus), Virginia opossums (Didelphis virginiana), eastern wild turkeys (Meleagris gallopavo silvestri), and fox squirrels (Sciurus niger). We performed real-time polymerase chain reaction (PCR) on fecal swabs, oral swabs, and tissues, including lung, liver, kidney, small intestine, large intestine, and when appropriate nasal turbinates, to detect ONRAB(®) DNA from inoculated animals. By seven days post-inoculation, turkeys, opossums, and cottontails had all stopped shedding ONRAB(®) DNA. One wood rat and one fox squirrel still had detectable levels of ONRAB(®) DNA in fecal swabs 14 days post-inoculation. Real-time PCR analysis of the tissues revealed some ONRAB(®) DNA persisting in certain tissues; however, there were no significant gross or histologic lesions associated with ONRAB(®) in any of the species studied. Our results suggest that many non-target species are not likely to be impacted by the distribution of ONRAB(®) as part of oral rabies vaccination programs in the United States.


Lower extremity biomechanics during weightlifting exercise vary across joint and load.
The purpose of this study was to determine the effect of load on lower extremity biomechanics during the pull phase of the clean. Kinematic and kinetic data of the 3 joints of the lower extremity were collected while participants performed multiple sets of cleans at 3 percentages: 65, 75, and 85% of 1 repetition maximum (1RM). General linear models with repeated measures were used to assess the influence of load on angular velocities, net torques, powers, and rates of torque development at the ankle, knee, and hip joint. The results suggest that the biomechanical demands required from the lower extremities change with the lifted load and to an extent depend on the respective joint. Most notably, the hip and knee extended significantly faster than the ankle independent of load, whereas the hip and ankle generally produced significantly higher torques than the knee did. Torque, rate of torque development (RTD), and power were maximimal at 85% of 1RM for the ankle joint and at 75% of 1RM for the knee joint. Torque and RTD at the hip were maximal at loads >75% of 1RM. This study provides important novel information about the mechanical demands of a weightlifting exercise and should be heeded in the design of resistance training programs.


Creating Supported Plasma Membrane Bilayers Using Acoustic Pressure.
Model membrane systems are essential tools for the study of biological processes in a simplified setting to reveal the underlying physicochemical principles. As cell-derived membrane systems, giant plasma membrane vesicles (GPMVs) constitute an intermediate model between live cells and fully artificial structures. Certain applications, however, require planar membrane surfaces. Here, we report a new approach for creating supported plasma membrane bilayers (SPMBs) by bursting cell-derived GPMVs using ultrasound within a microfluidic device. We show that the mobility of outer leaflet molecules is preserved in SPMBs, suggesting that they are accessible on the surface of the bilayers. Such model membrane systems are potentially useful in many applications requiring detailed characterization of plasma membrane dynamics.


Proposed Method for Development of Small Female and Midsize Male Thorax Dynamic Response Corridors in Side and Forward Oblique Impact Tests.
Despite the increasing knowledge of the thorax mechanics, the effects of inter-individual differences on the mechanical response are difficult to take into account. Several methods are available in the literature to refine the biofidelity corridors or to extrapolate them to other populations (eg: children, small females, large males). Because of the lack of concrete cases, the relevance of the assumptions is rarely investigated. In 2014, Baudrit et al. published data on thorax dynamic responses of small female and midsize male Post Mortem Human Subjects in side and forward oblique impact tests. The impactor mass was 23.4 kg for all the tests and the nominal impact speed was 4.3 m/s. The diameter of the rigid disk was 130 and 152 mm respectively for the small female specimens and for the midsize male specimens. The authors found that the maximum impact force was a function of the total body mass for each loading. They also reported that the ratio of dissipated energy on total deformation energy was almost constant and equal to 0.88. From these observations, a method was developed to aggregate data of the whole PMHS sample and to construct force time history and deflection time history corridors, for the 50th male and the 5th female, in pure lateral and in forward oblique tests. These corridors are provided in the paper and compared to the literature. Scaling factors derived from the corridors are also provided and used to evaluate the assumptions associated with the corridors provided in the literature.


Timely follow-up of abnormal diagnostic imaging test results in an outpatient setting: are electronic medical records achieving their potential?
Given the fragmentation of outpatient care, timely follow-up of abnormal diagnostic imaging results remains a challenge. We hypothesized that an electronic medical record (EMR) that facilitates the transmission and availability of critical imaging results through either automated notification (alerting) or direct access to the primary report would eliminate this problem. We studied critical imaging alert notifications in the outpatient setting of a tertiary care Department of Veterans Affairs facility from November 2007 to June 2008. Tracking software determined whether the alert was acknowledged (ie, health care practitioner/provider [HCP] opened the message for viewing) within 2 weeks of transmission; acknowledged alerts were considered read. We reviewed medical records and contacted HCPs to determine timely follow-up actions (eg, ordering a follow-up test or consultation) within 4 weeks of transmission. Multivariable logistic regression models accounting for clustering effect by HCPs analyzed predictors for 2 outcomes: lack of acknowledgment and lack of timely follow-up. Of 123 638 studies (including radiographs, computed tomographic scans, ultrasonograms, magnetic resonance images, and mammograms), 1196 images (0.97%) generated alerts; 217 (18.1%) of these were unacknowledged. Alerts had a higher risk of being unacknowledged when the ordering HCPs were trainees (odds ratio [OR], 5.58; 95% confidence interval [CI], 2.86-10.89) and when dual-alert (>1 HCP alerted) as opposed to single-alert communication was used (OR, 2.02; 95% CI, 1.22-3.36). Timely follow-up was lacking in 92 (7.7% of all alerts) and was similar for acknowledged and unacknowledged alerts (7.3% vs 9.7%; P = .22). Risk for lack of timely follow-up was higher with dual-alert communication (OR, 1.99; 95% CI, 1.06-3.48) but lower when additional verbal communication was used by the radiologist (OR, 0.12; 95% CI, 0.04-0.38). Nearly all abnormal results lacking timely follow-up at 4 weeks were eventually found to have measurable clinical impact in terms of further diagnostic testing or treatment. Critical imaging results may not receive timely follow-up actions even when HCPs receive and read results in an advanced, integrated electronic medical record system. A multidisciplinary approach is needed to improve patient safety in this area.


Efficient Conversion of Carbon Dioxide by Imidazolium-Based Cross-Linked Nanostructures Containing Polyhedral Oligomeric Silsesquioxane (POSS) Building Blocks.
Polyhedral oligomeric silsesquioxanes (POSS) have been employed as molecular building blocks for the synthesis of imidazolium cross-linked networks, to be used as heterogeneous catalysts for the conversion of carbon dioxide into cyclic carbonates. Two hybrid materials with different nucleophilic species (bromide and iodide) have been prepared and characterized by means of elemental analysis, 13 C and 29 Si solid-state NMR spectroscopy, thermogravimetric analysis and IR spectroscopy. The solids were tested as the sole catalyst under metal- and solvent-free reaction conditions showing full selectivity toward the formation of cyclic carbonates. High turnover number (TON) and productivity values, up to 5502 and 1081 respectively for glycidol conversion at 100 °C and up to 4942 and 1122 for epichlorohydrin conversion at 150 °C after 3 h, were obtained. Such outstanding productivity values were ascribed to the optimal organic/inorganic (i. e., imidazolium moiety/POSS support) weight ratio. The recyclability of the materials was successfully verified for five consecutive runs allowing their consideration as promising candidates for continuous flow technologies.


Evaluation of effect of entropy monitoring on isoflurane consumption and recovery from anesthesia.
Entropy monitoring entails measurement of the effect of anesthetic on its target organ rather than merely the concentration of anesthetic in the brain (indicated by alveolar concentration based on which minimum alveolar concentration [MAC] is displayed). We proposed this prospective randomised study to evaluate the effect of entropy monitoring on isoflurane consumption and anesthesia recovery period. Sixty patients undergoing total abdominal hysterectomy under general anesthesia using an endotracheal tube were enrolled in either clinical practice (CP) or entropy (E) group. In group CP, isoflurane was titrated as per clinical parameters and MAC values, while in Group E, it was titrated to entropy values between 40 and 60. Data including demographics, vital parameters, alveolar isoflurane concentration, MAC values, entropy values, and recovery profile were recorded in both groups. Demographic data and duration of surgery were comparable. Time to eye opening on command and time to extubation (mean ± standard deviation) were significantly shorter, in Group E (6.6 ± 3.66 and 7.27 ± 4.059 min) as compared to Group CP (9.77 ± 5.88 and 11.63 ± 6.90 min), respectively. Mean isoflurane consumption (ml/h) was 10.81 ± 2.08 in Group E and 11.45 ± 2.24 in Group CP and was not significantly different between the groups. Time to readiness to recovery room discharge and postanesthesia recovery scores were also same in both groups. Use of entropy monitoring does not change the amount of isoflurane consumed during maintenance of anesthesia or result in clinically significant faster recovery.


In vitro fermentation and prebiotic potential of novel low molecular weight polysaccharides derived from agar and alginate seaweeds.
Fermentation properties and prebiotic potential of novel low molecular weight polysaccharides (LMWPs) derived from agar and alginate bearing seaweeds was investigated. Ten LMWPs were supplemented to pH, temperature controlled anaerobic batch cultures inoculated with human feces from three donors, in triplicate. Microbiota changes were monitored using Fluorescent in-situ hybridization and short chain fatty acids, the fermentation end products were analysed using gas chromatography. Of the ten LMWPs tested, Gelidium seaweed CC2253 of molecular weight 64.64 KDa showed a significant increase in bifidobacterial populations from log(10) 8.06 at 0 h to log(10) 8.55 at 24 h (p = 0.018). For total bacterial populations, alginate powder CC2238 produced a significant increase from log(10) 9.01 at 0 h to log(10) 9.58 at 24 h (p = 0.032). No changes were observed in the other bacterial groups tested viz. Bacteroides, Lactobacilli/Enterococci, Eubacterium rectale/Clostridium coccoides and Clostridium histolyticum. The polysaccharides also showed significant increases in total SCFA production, particularly acetic and propionic acids, indicating that they were readily fermented. In conclusion, some LMWPs derived from agar and alginate bearing seaweeds were fermented by gut bacteria and exhibited potential to be used a novel source of prebiotics.


Practical considerations of using topical honey for neuropathic diabetic foot ulcers: a review.
It is increasingly important to identify and use low-cost effective dressings for treating diabetic foot ulcers as medical costs and rates of diabetes continue to rise. Honey is an inexpensive moist dressing with antibacterial and tissue-healing properties that has shown promise in the medical literature. Many clinicians are unfamiliar with its use, but patients with diabetic foot ulcers may wish to try honey therapy or discuss it with their physicians. The purpose of this review is to familiarize physicians with practical aspects of using honey to treat diabetic foot ulcers. The authors have experience using topical honey and are currently conducting a randomized controlled trial of its effectiveness in treating diabetic foot ulcers. In this review, the authors summarize evidence of honey's effectiveness, its hypothesized mechanism of action, potential risks and benefits, the types of honey available, and the nature of its application. Critical aspects of ulcer care are also reviewed. Honey is a low-cost topical therapy with important potential for healing. Its use may be considered in diabetic foot ulcers after a discussion of risks and benefits and in conjunction with standard wound care principles.


Bistability of time-periodic polarization dynamics in a free-running VCSEL.
We report experimentally a bistability between two limit cycles (i.e. time-periodic dynamics) in a free-running vertical-cavity surface-emitting laser. The two limit cycles originate from a bifurcation on two elliptically polarized states which exhibit a small frequency difference and whose main axes are symmetrical with respect to the linear polarization eigenaxes at threshold. We demonstrate theoretically that this peculiar behavior can be explained in the framework of the spin-flip model model by taking into account a small misalignment between the phase and amplitude anisotropies.


Microvascular endothelial cells of the corpus luteum.
The cyclic nature of the capillary bed in the corpus luteum offers a unique experimental model to examine the life cycle of endothelial cells, involving discrete physiologically regulated steps of angiogenesis, blood vessel maturation and blood vessel regression. The granulosa cells and theca cells of the developing antral follicle and the steroidogenic cells of the corpus luteum produce and respond to angiogenic factors and vasoactive peptides. Following ovulation the neovascularization during the early stages of corpus luteum development has been compared to the rapid angiogenesis observed during tumor formation. On the other end of the spectrum, the microvascular endothelial cells are the first cells to undergo apoptosis at the onset of corpus luteum regression. Important insights on the morphology and function of luteal endothelial cells have been gained from a combination of in vitro and in vivo studies on endothelial cells. Endothelial cells communicate with cells comprising the functional unit of the corpus luteum, i.e., other vascular cells, steroidogenic cells, and immune cells. This review is designed to provide an overview of the types of endothelial cells present in the corpus luteum and their involvement in corpus luteum development and regression. Available evidence indicates that microvascular endothelial cells of the corpus luteum are not alike, and may differ during the process of angiogenesis and angioregression. The contributions of vasoactive peptides generated by the luteal endothelin-1 and the renin-angiotensin systems are discussed in context with the function of endothelial cells during corpus luteum formation and regression. The ability of two cytokines, tumor necrosis factor alpha and interferon gamma, are evaluated as paracrine mediators of endothelial cell function during angioregression. Finally, chemokines are discussed as a vital endothelial cell secretory products that contribute to the recruitment of eosinophils and macrophages. The review highlights areas for future investigation of ovarian microvascular endothelial cells. The potential clinical applications of research directed on corpus luteum endothelial cells are intriguing considering reproductive processes in which vascular dysfunctions may play a role such as ovarian failure, polycystic ovary syndrome (PCOS), and ovarian hyperstimulation syndrome (OHSS).


Effects of nicotine on canine intestinal blood flow and oxygen consumption.
The purpose of this study was to determine the effects of nicotine on intestinal blood flow and oxygen consumption. The intravenous infusion of nicotine at doses corresponding to those experienced by smokers produced a transient increase in systemic arterial blood pressure and mesenteric blood flow. Subsequently a steady-state response developed that consisted of a reduction in mesenteric blood flow due to both a decrease in blood pressure and an increase in intestinal vascular resistance. This increase in resistance was probably due to increased levels of circulating catecholamines. The intra-arterial infusion of nicotine into the intestinal circulation at doses experienced by the average smoker had no effect on either intestinal blood flow or oxygen consumption. Similarly, under in vitro conditions nicotine had no direct effect on intestinal vascular smooth muscle tension. Thus, nicotine appears to reduce intestinal blood flow indirectly as a result of its systemic effects.


Have health human resources become more equal between rural and urban areas after the new reform?
The lack of health human resources is a global issue. China also faces the same issue, in addition to the equity of human resources allocation. With the launch of new healthcare reform of China in 2009, have the issues been improved? Relevant data from China Health Statistical Yearbook and a qualitative study show that the unequal allocation of health human resources is getting worse than before.


Evaluation of Omics-Based Strategies for the Management of Advanced Lung Cancer.
Omic-informed therapy is being used more frequently for patients with non-small-cell lung cancer (NSCLC) being treated on the basis of evidence-based decision-making. However, there is a lack of a standardized framework to evaluate those decisions and understand the association between omics-based management strategies and survival among patients. Therefore, we compared outcomes between patients with lung adenocarcinoma who received omics-driven targeted therapy versus patients who received standard therapeutic options. This was a retrospective study of patients with advanced NSCLC adenocarcinoma (N = 798) at City of Hope who received genomic sequencing at the behest of their treating oncologists. A thoracic oncology registry was used as a clinicogenomic database to track patient outcomes. Of 798 individuals with advanced NSCLC (median age, 65 years [range, 22-99 years]; 60% white; 50% with a history of smoking), 662 patients (83%) had molecular testing and 439 (55%) received targeted therapy on the basis of the omic-data. A fast-and-frugal decision tree (FFT) model was developed to evaluate the impact of omics-based strategy on decision-making, progression-free survival (PFS), and overall survival (OS). We calculated that the overall positive predictive value of the entire FFT strategy for predicting decisions regarding the use of tyrosine kinase inhibitor-based targeted therapy was 88% and the negative predictive value was 96%. In an adjusted Cox regression analysis, there was a significant correlation with survival benefit with the FFT omics-driven therapeutic strategy for both PFS (hazard ratio [HR], 0.56; 95% CI, 0.42 to 0.74; P < .001) and OS (HR, 0.51; 95% CI, 0.36 to 0.71; P < .001) as compared with standard therapeutic options. Among patients with advanced NSCLC who received care in the academic oncology setting, omics-driven therapy decisions directly informed treatment in patients and was correlated with better OS and PFS.


Changes in macromolecular allocation in nondividing algal symbionts allow for photosynthetic acclimation in the lichen Lobaria pulmonaria.
• The lichen Lobaria pulmonaria survives large seasonal environmental changes through physiological acclimation to ambient conditions. • We quantitated algal cell population, cell division and key macromolecular levels associated with photosynthesis and nitrogen metabolism in L. pulmonaria sampled from four seasons with contrasting environmental conditions in a deciduous forest. • The algal symbiont population did not vary seasonally and cell division was restricted to the newest thallus margins. Nevertheless the symbiont concentrations of chlorophyll, PsbS, PsbA, and RbcL changed significantly through the seasons in the nondividing algal cells from older thallus regions. • L. pulmonaria reversibly allocated resources toward photochemical electron generation and carbohydrate production through the spring, summer and fall, and towards photoprotective dissipation in the cold, high-light winter. Our study shows that large seasonal molecular acclimation in L. pulmonaria occurs within a nearly stable, nondividing algal cell population that maintains photosynthetic capacity through many years of changing environmental cues.


The E2F functional analogue SBF recruits the Rpd3(L) HDAC, via Whi5 and Stb1, and the FACT chromatin reorganizer, to yeast G1 cyclin promoters.
Regulation of the CLN1 and CLN2 G1 cyclin genes controls cell cycle progression. The SBF activator binds to these promoters but is kept inactive by the Whi5 and Stb1 inhibitors. The Cdc28 cyclin-dependent kinase phosphorylates Whi5, ending the inhibition. Our chromatin immunoprecipitation (ChIP) experiments show that SBF, Whi5 and Stb1 recruit both Cdc28 and the Rpd3(L) histone deacetylase to CLN promoters, extending the analogy with mammalian G1 cyclin promoters in which Rb recruits histone deacetylases. Finally, we show that the SBF subunit Swi6 recruits the FACT chromatin reorganizer to SBF- and MBF-regulated genes. Mutations affecting FACT reduce the transient nucleosome eviction seen at these promoters during a normal cell cycle and also reduce expression. Temperature-sensitive mutations affecting FACT and Cdc28 can be suppressed by disruption of STB1 and WHI5, suggesting that one critical function of FACT and Cdc28 is overcoming chromatin repression at G1 cyclin promoters. Thus, SBF recruits complexes to promoters that either enhance (FACT) or repress (Rpd3L) accessibility to chromatin, and also recruits the kinase that activates START.


Evaluation of parameters of oxidative stress after in vitro exposure to FMCW- and CDMA-modulated radiofrequency radiation fields.
The goal of this study was to determine whether radiofrequency (RF) radiation is capable of inducing oxidative stress or affecting the response to oxidative stress in cultured mammalian cells. The two types of RF radiation investigated were frequency-modulated continuous-wave with a carrier frequency of 835.62 MHz (FMCW) and code division multiple access centered on 847.74 MHz (CDMA). To evaluate the effect of RF radiation on oxidative stress, J774.16 mouse macrophage cells were stimulated with gamma-interferon (IFN) and bacterial lipopolysaccharide (LPS) prior to exposure. Cell cultures were exposed for 20-22 h to a specific absorption rate of 0.8 W/kg at a temperature of 37.0 +/- 0.3 degrees C. Oxidative stress was evaluated by measuring oxidant levels, antioxidant levels, oxidative damage and nitric oxide production. Oxidation of thiols was measured by monitoring the accumulation of glutathione disulfide (GSSG). Cellular antioxidant defenses were evaluated by measuring superoxide dismutase activity (CuZnSOD and MnSOD) as well as catalase and glutathione peroxidase activity. The trypan blue dye exclusion assay was used to measure any changes in viability. The results of these studies indicated that FMCW- and CDMA-modulated RF radiation did not alter parameters indicative of oxidative stress in J774.16 cells. FMCW- and CDMA-modulated fields did not alter the level of intracellular oxidants, accumulation of GSSG or induction of antioxidant defenses in IFN/LPS-stimulated cells. Consistent with the lack of an effect on oxidative stress parameters, no change in toxicity was observed in J774.16 cells after either optimal (with or without inhibitors of nitric oxide synthase) or suboptimal stimulation.


Regional Anaesthesia Is Associated with Shorter Postanaesthetic Care and Less Pain Than General Anaesthesia after Upper Extremity Surgery.
Introduction. For surgery on the upper extremity, the anaesthetist often has a choice between regional anaesthesia (RA) and general anaesthesia (GA). We sought to investigate the possible differences between RA and GA after upper extremity surgery with regard to postoperative patient comfort. Methods. This is a retrospective observational study that was performed at an acute care secondary referral centre. One hundred and eighty-seven procedures involving orthopaedic surgery on the upper extremity were included. The different groups (RA and GA) were compared regarding the primary outcome variable, length of stay in Postanaesthesia Unit, and secondary outcome variables, opioid consumption and nausea treatment. Results. RA was associated with significantly shorter median length of stay (99 versus 171 minutes). In the GA group, 32% of the patients received opioid analgesics and 21% received antiemetics. In the RA group, none received opioid analgesics and 3% received antiemetics. Conclusion. In this observational study, RA was superior to GA for surgery of the upper extremity regarding Postanaesthesia Care Unit length of stay, number of doses of analgesic, and number of doses of antiemetic administered.


Mapping immune processes in intact tissues at cellular resolution.
Understanding the spatiotemporal changes of cellular and molecular events within an organism is crucial to elucidate the complex immune processes involved in infections, autoimmune disorders, transplantation, and neoplastic transformation and metastasis. Here we introduce a novel multicolor light sheet fluorescence microscopy (LSFM) approach for deciphering immune processes in large tissue specimens on a single-cell level in 3 dimensions. We combined and optimized antibody penetration, tissue clearing, and triple-color illumination to create a method for analyzing intact mouse and human tissues. This approach allowed us to successfully quantify changes in expression patterns of mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and T cell responses in Peyer's patches following stimulation of the immune system. In addition, we employed LSFM to map individual T cell subsets after hematopoietic cell transplantation and detected rare cellular events. Thus, we present a versatile imaging technology that should be highly beneficial in biomedical research.


Comparative Efficacy of Treatment Options for the Prevention of Post-TIPS Hepatic Encephalopathy: A Systematic Review and Network Meta-analysis.
Transjugular intrahepatic portosystemic shunt (TIPS) is often used in patients with cirrhosis to manage portal hypertension-related complications. Unfortunately, 35-50% of patients develop overt hepatic encephalopathy (HE) after TIPS. However, data on lactulose and rifaximin to prevent post-TIPS HE is limited. Therefore, we aimed to perform a network meta-analysis to investigate the efficacy of multiple pharmacological regimens in the prevention of post-TIPS HE. A comprehensive search strategy to identify reports of studies of rifaximin use on post-TIPS hepatic encephalopathy was constructed using truncated keywords, phrases, and subject headings developed in Embase. This strategy was translated to MEDLINE, Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection, with all searches performed on 10 February 2022. No publication date or language limits were used. The initial search identified 72 studies, and 56 studies were screened after removing duplicates. Five studies, two randomized controlled trials (RCTs) and three retrospective studies, met our inclusion criteria and were included in the final analysis. A total of 840 patients were included, with 65% male. Our meta- analysis did not find a statistically significant difference between lactulose vs placebo/no prophylaxis, nor rifaximin vs placebo/no prophylaxis, nor rifaximin plus lactulose vs placebo/no prophylaxis in the reduction of post-TIPS HE. Rifaximin alone, lactulose alone, and rifaximin plus lactulose did not significantly reduce the development of post-TIPS HE. Based on the P-scores of the three treatment groups, the combination of rifaximin plus lactulose showed the most promising trend towards preventing post-TIPS HE. More studies, especially large RCTs, are warranted.


Eruptive tufted angiomas in a patient with Crohn's disease.
Angioblastoma is a rare, benign vascular tumour composed of undifferentiated mesenchymal cells with a tendency to form lumina. This entity was first described by Nakagawa in 1949 as angioblastoma, and Wilson Jones was the first to use the term "tufted angioma" in 1976. Tufted angiomas usually occur in infancy and spread slowly. This report describes lesions from the right side of the forehead, forearms, and thighs of a 24 year old man with a four year history of Crohn's disease, who was receiving infliximab in addition to long standing azathioprine and ciprofloxacillin. He developed numerous small itchy erythematous vascular appearing papules, which on histological examination resembled tufted angiomas, showing the classic "cannon ball" appearance. The lesions regressed within three months. This case may represent an eruptive acquired tufted angioma in which immunosuppression or drug induced modification of angiogenesis played a role in its development and regression. One previous case of eruptive tufted angioma has been reported in an immunosuppressed patient.